AUGUST 2010 • Vol. 2 • No. 5

Journal of the Society of PhySicianS of hong Kong

SPecial iSSue: PSychiatry & neurology

ISSN 2072-4209

www.sophysicianshk.orgVisit the web site for our regular CME programmes for doctors

香港內科學會THE SOCIETY OF PHYSICIANS OF HONG KONG

• MajorDepressiveDisorder–TreatmentOptionsOtherThanSSRI

Dr Lam Tat Chung, Paul (林達聰醫生)

• Long-termTreatmentofRelapsing-RemittingMultipleSclerosis

Dr Chan Koon Ho (陳灌豪醫生)

• ThePatientWithDailyHeadache

Dr Hui Che Fai, Andrew (許志輝醫生)

CONTENTS

54 MajorDepressiveDisorder–TreatmentOptionsOtherThanSSRI

Dr Lam Tat Chung, Paul (林達聰醫生)

58 Long-termTreatmentofRelapsing-RemittingMultipleSclerosis

Dr Chan Koon Ho (陳灌豪醫生)

62 ThePatientWithDailyHeadache Dr Hui Che Fai, Andrew (許志輝醫生)

Journal of the Society of PhySicianS of hong Kong

August 2010 • Vol. 2 • No. 5Special Issue: Psychiatry & Neurology

www.sophysicianshk.org

香港內科學會THE SOCIETY OF PHYSICIANS OF HONG KONG

ExEcuTIvEcOMMITTEE

PRESIDENTDrLamTatchung,Paul林達聰醫生

VIcE PRESIDENTDrTsangWahTak,Kenneth曾華德醫生

HoN. SEcRETaRyDrShiuchoTak,Wesely邵祖德醫生

HoN. TREaSuRERDrLamHowMo,Ignatius林孝武醫生

cHIEF EDIToRDrLauchuPak劉柱柏醫生

EDIToRSDrchanchunKwong,Jane陳真光醫生DrchanHinLee,Henry陳衍里醫生DrchanKwokWing,Fredriech陳國榮醫生DrchanPuiYiu,Nicola陳珮瑤醫生DrchanTakHin陳德顯醫生DrchenYiTin陳以天醫生DrLamcheungcheung,Barbara藍章翔醫生DrLamTatchung,Paul林達聰醫生DrLamTseFun,cathy林紫芬醫生DrLeungWaiKeung梁偉強醫生DrLiSiuLung,Steven李少隆醫生DrSheaTatMing,Paul佘達明醫生DrShiuchoTak,Wesely邵祖德醫生DrTamKwokKuen,vincent譚國權醫生DrTsangWahTak,Kenneth曾華德醫生

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EditorialIn primary care settings, approximately 30% to 50% of patients have prominent psy-chiatric symptoms or identifiable mental disorders, which are of significant adverse consequences if left untreated.1 Even in surgical specialties, many presurgical and postsurgical developments are associated with significant mental health issues. Recent trends in medicine promote the further integration of psychiatry into the main-stream of medical practice, and emphasize the importance of attending to patients with psychiatric symptoms regardless of the clinician’s medical specialty.2 We hope this issue of the Journal will remind our readers of this important aspect of patient care.

References:1. Weissman MM, Neria Y, Gameroff JJ, et al. Positive screens for psychiatric disorders in primary care: A long-term follow-up of patients who were not in

treatment. Psychiatr Serv 2010;61:151-159.2. David Kupfer, Darrel Regier. Why all of medicine should care about DSM-5. JAMA 2010;303:1974-1975.

Dr lam Tat Chung, Paul林達聰醫生FRCP, FHKAM (Medicine), FHKAM (Psychiatry)President

Dr lau Chu Pak 劉柱柏醫生FRCP, MD, FHKAM (Medicine) Chief Editor

54 Journal of The Society of Physicians of Hong Kong

MajorDepressiveDisorder–TreatmentOptionsOtherThanSSRI

Depression is a complex syndrome that includes many different symptoms. With depressive mood as a core symptom, the

condition is also associated with tiredness, loss of drive and motivation, poor con-centration and cognitive functioning, impairment of attention or alertness, an-hedonia and sexual dysfunction, agitation and irritability, aggression, anxiety, hyper-somnia or insomnia, feeling of guilt, sui-cidality, dyscontrol of appetite and weight, and many associated physical symptoms.

The pharmacological treatment of depression evolves around the un-derstanding and manipulation of the monoamine systems, namely the sero-tonergic, noradrenergic and dopaminergic systems. The interplay between these systems is not fully understood, but the adequacy and proper functioning of each of the monoamines has been shown to be important for the maintenance of a normal mood. Drugs have been developed to target each of the three systems to al-leviate the disorder.

Currently, the most widely pre-scribed group of drugs for the treatment of depression is the selective serotonin reuptake inhibitors (SSRIs). This group of drugs is deemed as a great advance over the older antidepressants such as monoamine oxidase inhibitors (MAOIs) and tricyclics in terms of side effect profile and safety. Though a welcomed addition to the armamentarium, there remains

many problems and inadequacies that need to be addressed or improved. These include the lack of efficacy in some pa-tients, sexual dysfunction, weight gain, sedation, withdrawal symptoms, etc.

In the Sequenced Treatment Alter-native to Relieve Depression (STAR*D) trial, an important large-scale study com-missioned by the US National Institute of Mental Health, treatment with the SSRI citalopram for about 10 weeks resulted in a remission rate of only around 30%.1

An amotivational syndrome has been described in patients following use of SSRIs for several months. In these patients, although the depression im-proved, a state of apathy and indifference developed, which could be temporarily al-leviated by a dose reduction of the SSRI. The addition of a noradrenergic agent im-proved the condition.2,3 Other problems included bleeding tendencies and the syndrome of inappropriate antidiuretic hormone secretion.

Alternative medications have been developed to address the shortcomings of the SSRIs, and for the group of patients who require treatment for certain specific symptoms in the depressive syndrome by tackling different monoaminergic systems. (Table) While some medications modulate the noradrenergic system, bu-propion is the only medication currently available that can effectively target the dopaminergic system as well. Different symptom groups that are controlled by

Keywords:SSRI (選擇性血清素再吸收抑制劑), major depressive disorder (重度抑鬱症), NDRI (去甲腎上腺素-多巴胺再吸收抑制劑)

Dr lam Tat Chung, Paul (林達聰醫生)FRCP, FHKAM(Medicine), FHKAM(Psychiatry)

Specialist in Psychiatry (Private Practice)

Hon. Clinical Assistant Professor, University of Hong Kong

Table.Neurotransmittereffectsofantidepressants

Norepinephrine/noradrenaline(NE) Serotonin(5-HT) Dopamine(DA)

SSRIs √

Bupropion SR √ √

Mirtazapine √ √

Nefazodone √ √

Venlafaxine √ √

SR = sustained release; SSRI = selective serotonin reuptake inhibitor

Journal of The Society of Physicians of Hong Kong 55

the three different monoamines are illus-trated in Figure 1.4

Bupropion is a monocyclic ami-noketone that has been used for the treatment of major depression since 1989. It belongs to the class of norepinephrine-dopamine reuptake in-hibitors (NDRIs). Sustained-release (SR) tablets (150 mg) were available in the US since 1996, and extended-release (XR) tablets (300 mg) since 2003.

Efficacy Studies

A pooled analysis of six randomized con-trolled trials showed that remission rate with bupropion was similar to SSRIs and better than placebo.5 (Figure 2) Other studies have shown comparable

remission rates with escitalopram and venlafaxine.6-9 (Figure 3) Bupropion has also been shown to confer superior benefit in patients complaining of reduced energy, pleasure and interest.10

Treatment Switching

In the STAR*D trial, switching to bu-propion SR, sertraline or venlafaxine resulted in similar remission rates of 26% to 28% in patients previously non- responsive to citalopram.11

Combination Therapy

In the above trial, the addition of bu-propion SR resulted in a remission rate

of 39% in patients previously not re-sponding to citalopram alone. This is much better than the remission rate of 32.9% with buspirone augmentation. Other more favourable outcomes with the bupropion combination include treatment adherence, adverse reaction and change in the Quick Inventory of De-pressive Symptomatology – Self Report (QIDS-SR) score.12

other Benefits

Sexual dysfunction occurs in 20% to 60 % of patients treated with SSRIs. This may pose significant distress to depressed patients and compromise their quality of life. Bupropion is not associated with sexual dysfunction including orgasmic dysfunction, sexual arousal disorder and sexual desire disorder.13

Most antidepressants including SSRIs, mirtazapine, tricyclics and MAOIs cause weight gain. No such adverse effect is observed with bupropion. The agent may induce more weight loss than placebo in obese adults.14

Anxiety frequently occurs in de-pressed patients. Bupropion SR compares favourably with SSRI in the control of anxiety symptoms.15

Figure1.Differentsymptomgroupscontrolledbyserotonin,noradrenalineanddopamine

Adapted from reference 4.

Rem

issi

on ra

te (%

) HA

M-D

7

Placebo (n=489)

34.1%

Bupropion XR (n=263)

43%*

Escitalopram (n=266)

45%*

Placebo (n=256)

34%

SSRI* (n=731)

48.7%***

Bupropion (n=662)

46.5%***

55504540353025201510

50

50

40

30

20

10

0

* p<0.05 vs placebo

Bupropion XR vs escitalopram

Pooled analysis of 2 identical trials

Patie

nts

with

HAM

D-17

7a

t w

eek

8 (%

)

Figure2.RemissionrateswithbupropionandSSRIs:Pooledanalysisof6RcTs

* Escitalopram (2), paroxetine (1), sertraline (3)** p<0.0001 vs placeboHAM-D = Hamilton Depression Rating Scale; RCT = randomized controlled trial; SSRI = selective serotonin reuptake inhibitor Adapted from reference 5.

Rem

issi

on ra

te (%

) HA

M-D

7

Placebo (n=489)

34.1%

Bupropion XR (n=263)

43%*

Escitalopram (n=266)

45%*

Placebo (n=256)

34%

SSRI* (n=731)

48.7%***

Bupropion (n=662)

46.5%***

55504540353025201510

50

50

40

30

20

10

0

* p<0.05 vs placebo

Bupropion XR vs escitalopram

Pooled analysis of 2 identical trials

Patie

nts

with

HAM

D-17

7a

t w

eek

8 (%

)

Figure3.RemissionrateswithbupropionxRvsescitalopram

“Remission rate with bupropion was similar

to SSRIs”

Neurotransmittersregulatemood,cognitionandbehaviour

NORADRENALINE Serotonin

DOPAMINE

VigilanceEnergy

Impulse

Anxiety

Irritability

MoodEmotion

cognitivefunction

Motivation

AppetiteSex

Aggression

attentionMotivationPleasure

HAMD-17 = 17-item Hamilton Depression Rating Scale; XR = extended release Adapted from reference 6.

56 Journal of The Society of Physicians of Hong Kong

Adverse Effects

The more frequent adverse effects are headache, insomnia, nausea, vomiting, dry mouth, and sweating.

Special Patient Groups

Bupropion has to be used with care in patients with hepatic failure or renal im-pairment. Caution should be exercised in patients prone to or with a history of seizure. The agent is classified under FDA Pregnancy Category B, while SSRIs are classified less favourably under Category C.

Conclusion

Bupropion SR (150 mg) given as a single morning dose is an appropriate and

efficacious choice for the treatment of patients with major depressive disorder, or for combination therapy with SSRIs. Its unique mechanism of noradrenergic and dopaminergic reuptake inhibition makes it an effective antidepressant, with special benefit for symptoms such as loss of energy and motivation, tiredness, hy-persomnia and anhedonia. It has special favourable profiles with regard to sexual function, body weight, control of anxiety symptoms and lack of sedation. In some patients, the dose can be increased to 150 mg twice daily if required.

References:1. Trivedi MH, Rush AJ, Wisniewski SR, et al; STAR*D Study Team.

Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice. Am J Psychiatry 2006;163:28-40.

2. Hoehn-Saric R, Lipsey JR, McLeod DR. Apathy and indifference in patients on fluvoxamine and fluoxetine. J Clin Psychopharmacol 1990;10:343-345.

3. Hoehn-Saric R, Harris GJ, Pearlson GD, Cox CS, Machlin SR, Camargo EE. A fluoxetine induced frontal lobe syndrome in an obsessive com-pulsive patient. J Clin Psychiatry 1991;52:131-133.

4. Healy D, McMonagle T. The enhancement of social functioning as a ther-apeutic principle in the management of depression. J Psychopharmacol 1997;11(4 suppl):S25-S31.

5. Papakostas GI, Nutt DJ, Hallett LA, Tucker VL, Krishen A, Fava M. Reso-lution of sleepiness and fatigue in major depressive disorder: A com-parison of bupropion and the selective serotonin reuptake inhibitors. Biol Psychiatry 2006;60:1350-1355.

6. Clayton AH, Croft HA, Horrigan JP, et al. Bupropion extended release compared with escitalopram: Effects on sexual functioning and anti-depressant efficacy in 2 randomized, double-blind, placebo-controlled studies. J Clin Psychiatry 2006;67:736-746.

7. Thase ME, Clayton AH, Haight BR, Thompson AH, Modell JG, Johnston JA. A double-blind comparison between bupropion XL and venlafaxine XR: Sexual functioning, antidepressant efficacy, and tolerability. J Clin Psychopharmcol 2006;26:482-488.

8. Hewett K, Chrzanowski W, Schmitz M, et al. Eight-week, placebo-controlled, double-blind comparison of the antidepressant efficacy and tolerability of bupropion XR and venlafaxine XR. J Psychopharmacol 2009;23:531-538

9. GlaxoSmithKline. Data on file.10. Jefferson JW, Rush AJ, Nelson JC, et al. Extended-release bupropion

for patients with major depressive disorder presenting with symptoms of reduced energy, pleasure, and interest: Findings from a randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2006;67: 865-873.

11. Rush AJ, Trivedi MH, Wisniewski SR, et al; STAR*D Study Team. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Eng J Med 2006;354:1231-1242.

12. Trivedi MH, Fava M, Wisniewski SR, et al; STAR*D Study Team. Medi-cation augmentation after the failure of SSRIs for depression. N Eng Med 2006;354:1243-1252.

13. Thase, et al. Presented at: 159th (NR-602) American Psychiatric Asso-ciation Annual Meeting; May 20-25, 2006; Toronto, Canada.

14. Anderson JW, Greenway FL, Fujioka K, Gadde KM, McKenney J, O’Neil PM. Bupropion SR enhances weight loss: A 48-week double-blind, placebo-controlled trial. Obes Res 2002;10:633-641.

15. Trivedi MH, Rush AJ, Carmody TJ, et al. Do bupropion SR and sertraline differ in their effects on anxiety in depressed patients? J Clin Psychiatry 2001;62:776-781.

THE SOCIETY OF PHYSICIANS OF HONG KONG

SUNDAY SYMPOSIUM SEPT 5, 2010 • 11:00 am-4:30 pm • Lunch 1:00 pm-2:00 pm

Nutritional and Supportive Care in Cancer Patients Dr. Shiu Cho Tak, Wesely, MD, FRCP 邵祖德醫生 Non-invasive Therapy of Cancer Professor Yu Chun Ho, Simon 余俊豪教授

Interventional Radiology in Cancer Management Dr. Lee Pui Keung 李沛強醫生

Cryoablation of Cancer Professor Niu Lizhi 牛立志教授

Nano-Embolization of Microvascular Vessels of Tumour Professor Piao Xiangghao 朴雙浩教授

Place : The Langham Hotel, 8 Peking Road, TST, Kowloon

Enquiry : Tel 2526 2626 (no telephone registration) CME points under application

Fee : Non-members please pay $50 on admission (do not mail your cheque).

Sponsor : Nestle Hong Kong Limited (open to medical doctors)

First come first served basis. Pre-registration is required. No confirmation will be sent for registration.

Unsuccessful applicants will be notified. Web registration and further details: www.SOPHYSICIANSHK.org

Registration form: Fax to 2504 2621 Attention: Ms Mandy Lo of Nestle

I wish to attend Sunday Symposium on Sept 5, 2010 ($50)

Name of Doctor (Surname first): Tel:

Free for Members and Associate Members on presentation of valid membership cards.

58 Journal of The Society of Physicians of Hong Kong

Long-termTreatmentofRelapsing-RemittingMultipleSclerosis

patients have oligoclonal bands (OCB) in cerebrospinal fluid (CSF).1,2 Asians have a lower prevalence of CMS than Caucasians; it has been reported that relatively higher proportions of Asian MS patients have opticospinal MS (OSMS), in which there is predominant involvement of optic nerves and spinal cord, and a lower frequency of CSF OCB.3,4 Recent evidence strongly suggests that OSMS is in fact neuromyelitis optica (NMO), also called Devic’s disease, which is distinct from CMS.5,6 RRMS patients develop recurrent attacks of inflammatory de-myelination affecting the cerebral hemi-spheres, brainstem, cerebellum, spinal cord (myelitis) and optic nerves (optic neuritis), which are associated with good neurological recovery especially in early attacks; in contrast, relapsing NMO pa-tients typically develop recurrent severe attacks of myelitis and optic neuritis as-sociated with early irreversible neuro-logical disabilities.6-8 Importantly, CMS patients are seronegative for NMO- immunoglobulin G (IgG), an autoantibody targeting the aquaporin-4 water channel and a specific biomarker for NMO, while about 60% to 73% of NMO patients are seropositive for NMO-IgG.5 Hence, early serological testing for NMO-IgG is useful in prompt diagnosis of NMO and its distinction from CMS in patients who present with myelitis or optic neuritis.5

Most RRMS patients have satis-factory recovery from acute attacks in the early phase; unfortunately, an accu-mulating number of patients will develop secondary progressive MS (SPMS) char-acterized by irreversible progressive neurological deterioration and disability accumulation with or without acute relapses.1,2,9,10 Natural history studies estimate that RRMS patients develop SPMS at a rate of 2% to 3% per year,1,2,9-17 and the median time to reach the Expanded Disability Status Scale

(EDSS) score of 6 (ie, need of unilateral assistance to walk for 100 metres) is es-timated to be about 19 years.14 Axonal degeneration is believed to be the key pathology underlying SPMS.18 Impor-tantly, axonal injury can occur and be severe early in RRMS.18-21 Hence, in the absence of effective treatments that can prevent or delay progression to SPMS, the majority of RRMS patients are at risk of significant neurological disability in the long term in view of the chronic nature and predominantly young onset age of this disorder.

Aetiological Factors

The exact pathogenetic mechanisms of MS are uncertain.1,2,22 Genetic factors contribute to its aetiology as evidenced by the concordance rate of 31% among monozygotic twins vs 5% for dizygotic twins; moreover, the presence of the HLA-DR2 antigen increases an indi-vidual’s susceptibility to CMS.2,23 Multiple genes influence the susceptibility to de-veloping MS, but no single gene with the possible exception of HLA has a strong influence.1,2

Environmental factors also play a role, as evidenced by the change in MS frequency among individuals and their offspring who migrate into and out of high-prevalence areas.24 Infection by micro-organisms including herpes simplex virus type 6 and Chlamydia pneumoniae is suggested to be a causative factor,25,26 but confirmation from other studies is lacking.

Diagnosis

The diagnosis of RRMS is suggested by a history of recurrent attacks of injury to different sites of the CNS, followed

Keywords:Relapsing-remitting multiple sclerosis (復發緩解型多發性硬化), beta-interferons (乙型干擾素), natalizumab

Dr Chan Koon Ho (陳灌豪醫生) MD (HK), MRCP (UK), MBBS (HK), FHKCP, FHKAM (Medicine), FRCP (Glasgow)

University Department of Medicine, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, University of Hong Kong

Research Centre of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, University of Hong Kong

Introduction

Multiple sclerosis (MS) is a chronic immune-mediated disorder characterized by in-flammatory demyelination of

the central nervous system (CNS).1,2 Ap-proximately 85% of patients with classical MS (CMS) have relapsing-remitting MS (RRMS) at onset, characterized by re-current attacks of inflammatory demyeli-nation and axonal injury affecting different sites of the CNS. About 90% of CMS

Journal of The Society of Physicians of Hong Kong 59

by partial or complete resolution of symptoms. Physical findings of abnor-malities at multiple CNS sites such as cer-ebellar ataxia from cerebellar involvement and paraparesis with a sensory level from spinal cord involvement support the di-agnosis. Magnetic resonance imaging (MRI) of multiple white matter lesions at different sites of the CNS (ie, spatial dissemination) and lesions with dif-ferent ages (ie, temporal dissemination, shown by new lesions on repeated MRI) greatly facilitate the diagnosis, especially in patients who presented with the first clinical attack, known as clinically isolated syndrome (CIS), based on fulfillment of the revised McDonald criteria.27 Lumbar puncture for exclusion of CNS infection and detection of CSF OCB helps to support the diagnosis. Other disorders that mimic RRMS must be excluded, especially relapsing NMO (by testing for NMO-IgG) and vasculitis such as cerebral lupus (by testing for autoimmune markers including antinuclear antibody [ANA] and anti-extractable nuclear antigen [anti-ENA] antibody).

Treatments

Aims and ApproachTreatment aims at: 1) reduction of relapse rate, 2) prevention of fixed disability di-rectly attributable to relapse, 3) symp-tomatic treatment of fixed neurological deficits, and 4) prevention or delay of development of SPMS, hence minimizing permanent disability. It is encouraged to adopt a multidisciplinary team approach, in which different professionals including neurologist, nurse specialist, physio-therapist, occupational therapist, rehabili-tation specialist and clinical psychologist contribute to patient care by providing expertise in management of a chronic neurological disorder. This review will address the long-term pharmacological treatment of RRMS.

long-term Disease-modifying Drugs Intravenous pulse methylprednisolone 0.25–1 g daily for 3 to 5 days is indicated during acute attacks associated with po-tentially significant disability to hasten neurological recovery; however, the

benefit on long-term neurological dis-ability is uncertain.1,2 Regular intermittent intravenous pulse corticosteroid and regular oral corticosteroid therapies are ineffective for reduction of relapse fre-quency. Currently, four disease-modifying drugs (DMDs) are approved for use in RRMS. These are beta-interferon (β-IFN) (1a and 1b), glatiramer acetate (GA), na-talizumab and mitoxantrone.2

Beta-interferon β-IFN 1a and 1b are first-line immuno-modulatory therapies for RRMS. Their short-term efficacy (for 2 to 3 years) in reducing relapse frequency by about one-third is well proven.28-30

β-IFN 1a and 1b possess anti-inflam-matory properties, inhibit T cell activation and reduce blood-brain barrier perme-ability to inflammatory cells.28 Therapy re-quires subcutaneous injection 3 times a week or on alternate days. Common side effects are local injection site reactions, flu-like symptoms with fever (which tend to subside after several weeks in most patients who continue with therapy), and reversible liver function derangement as evidenced by raised parenchymal liver enzyme levels.28 In addition, 5% to 30% of treated patients develop persistent neutralizing antibodies that are asso-ciated with reduced treatment effect on relapse frequency.2 Long-term benefits in prevention or reduction of disability are uncertain, and patients or carers need to perform subcutaneous injection. The ideal timing for starting β-IFN in RRMS is controversial.31,32 The author is in favour of early initiation of DMD once the di-agnosis of RRMS is confirmed and when the disease is active, as evidenced by clinical relapse or MRI evidence of sub-clinical active inflammation.

Glatiramer Acetate GA is a synthetic co-polymer structurally similar to myelin basic protein (MBP). Therapy requires daily subcutaneous injection. GA is thought to induce T cell anergy, inhibition of MBP-reactive T lym-phocytes and induction of T helper 2 lym-phocytes, resulting in an anti-inflammatory action.33 GA reduces relapse frequency of RRMS by about 30%, and improves MRI parameters of disease activity. Its efficacy is similar to that of β-IFN. GA is generally

safe and well tolerated. Similar to β-IFN, its benefit on long-term disability is uncertain.

NatalizumabLymphocyte migration across the blood-brain barrier is an important early step in the formation of lesions in MS.1,22 α4 integrins are a family of adhesion mol-ecules expressed on the surface of lym-phocytes, functioning as an important mediator of cell adhesion and transen-dothelial migration, and a regulator of immune cells activation within inflamed tissue.34,35 Natalizumab is a humanized monoclonal antibody against the α4 in-tegrins, which selectively blocks the binding of α4β1 and α4β7 integrins to their endothelial receptors, hence inhibiting migration of lymphocytes into the brain and reducing inflammation.

A randomized double-blind trial of 213 patients with RRMS or relapsing SPMS treated with intravenous natal-izumab (3 mg/kg or 6 mg/kg) or placebo every 28 days for 6 months showed that active treatment was associated with reductions in relapse frequency and the number of new enhancing brain lesions over the 6-month period. However, such differences disappeared upon an addi-tional 6 months’ follow-up.36

More recently, natalizumab was shown to be effective in RRMS by re-ducing the relapse rate at 1 year by 68%, and the risk of sustained progression of disability by 42% over 2 years in a 2-year phase III clinical trial.37 The cumulative probability of progression was 17% in the natalizumab group vs 29% in the placebo group. Furthermore, the addition of na-talizumab to β-IFN 1a reduced the risk of disability progression by 24% and annu-alized relapse rate by 55% over a 2-year period, compared with β-IFN 1a alone.38

Currently, natalizumab is recom-mended for RRMS patients who failed to respond to β-IFN, or RRMS patients with very aggressive disease that may be sta-bilized with natalizumab first followed by stepping down of therapy to β-IFN or GA. Some patients will develop neutralizing antibodies against natalizumab, which may cause hypersensitivity reactions and loss of drug efficacy over time. Patients reacting to or showing poor response to natalizumab may need testing for anti-

60 Journal of The Society of Physicians of Hong Kong

bodies. Importantly, patients treated with natalizumab, especially when preceded by other immunosuppressant therapy or used in combination with β-IFN, rarely develop progressive multifocal leukoen-cephalopathy (PML) due to latent JC virus infection. The risk of PML related to na-talizumab therapy is estimated to be 1 in 1,000 (0.1%) over an 18-month treatment period.39 It is generally accepted that the beneficial effects of natalizumab in active RRMS outweigh the risk of PML.40

Mitoxantrone Mitoxantrone is a synthetic anthra-cenedione with cytotoxic and immu-nosuppressive effects. It inhibits DNA repair and synthesis in dividing and non-dividing cells by inhibiting DNA topoi-somerase II, suppresses T and B cells, induces apoptosis in antigen-presenting cells, and deactivates macrophages.41,42 A randomized double-blind trial of 194 patients with worsening RRMS or SPMS treated with mitoxantrone (5 mg/m2 or 12 mg/m2) or placebo 3-monthly for 2 years showed that mitoxantrone offered significant benefits over placebo for the primary outcome, which was a com-posite of five clinical measures: ambu-lation index, standard neurological status, change from baseline in EDSS, number of relapses treated with corticosteroids, and time to first treated relapse.43

Mitoxantrone provides short-term benefits by reducing relapse rate, devel-opment of new cerebral lesions on MRI, and number of patients who experience deterioration of neurological function.43-45 However, these studies were in a relatively small number of patients, and benefits on disability were not established.

Serious potential side effects of mitoxantrone include dose-related im-pairment of left ventricular ejection fraction and irreversible congestive heart failure when the cumulative lifetime dose exceeds 140 mg/m2 (use of mitoxantrone is limited to a maximum of 3 years at current dosage), birth defects when given during pregnancy or time of conception to both male and female partners, ste-rility that may be permanent, and rarely leukaemia.

Mitoxantrone is recommended for use as induction therapy in very active RRMS or as rescue treatment if patients

do not respond to β-IFN or GA. It is licensed in the US for use in aggressive RRMS patients and SPMS patients with high relapse frequency, and recom-mended for patients with unsatisfactory response to high-dose β-IFN or those with rapidly progressive disease.46 Most recently, serious side effects of mitox-antrone, including congestive heart failure and therapy-related acute leukaemia, are reported to be more frequent than pre-viously believed.47 With the availability of natalizumab, mitoxantrone use is be-coming uncommon and less preferred.

Conclusion

DMDs should be considered for RRMS patients with active disease, but the timing of therapy initiation and the choice of DMDs should be individualized in view of differences in disease severity, relapse frequency, lifestyles, personal preference and funding support for these expensive therapies.

References:1. Noseworthy JH, Lucchinetti CF, Rodriguez M, Weinshenker BG. Multiple

sclerosis. N Eng J Med 2000;343:938-952.2. Compston A, Coles A. Multiple sclerosis. Lancet 2008;372:1502-1517.3. Yu YL, Woo E, Hawkins BR, Ho HC, Huang CY. Multiple sclerosis amongst

Chinese in Hong Kong. Brain 1989;112(pt 6):1445-1467.4. Kira J. Multiple sclerosis in the Japanese population. Lancet Neurol

2003;2:117-127.5. Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody

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62 Journal of The Society of Physicians of Hong Kong

ThePatientWithDailyHeadache

Dr Hui Che Fai, Andrew (許志輝醫生)MBBS (Lond), DTM&H, FHKAM, FHKCP, FRCP (Edin), FRCP (Lond)

Specialist in Neurology, PacifiCare

Key words: Migraine (偏頭痛), headache (頭痛)

Introduction

Physicians often come across patients who complain of frequent headaches. Most have episodic pain, but sometimes

the headaches are present on a daily basis. Chronic daily headache (CDH) is a common problem, affecting around 5% of the general population; children as well as adults may be affected. It is not a single entity but a heterogeneous group of disorders, occurring by definition 15 days per month for over 3 months.1,2

Primary headaches refer to dis-orders that have no clear structural cause and are described as “benign”, but the associated disability can be substantial – depression, anxiety, impaired occupa-tional and physical status. Primary CDH is categorized according to the duration of each episode – whether they last longer or shorter than 4 hours. (Table 1) Some headaches last for only a few seconds or minutes, the most well known of which is trigeminal neuralgia. Others include cluster headache, hypnic headache, par-oxysmal hemicrania, primary stabbing headache, and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing syndrome (SUNCT). The focus of this article is the first category in which episodes last for more than 4 hours. In this group, there are four forms of headache disorders: chronic mi-graine (previously called transformed mi-graine), chronic tension-type headache, new daily-persistent headache and hemi-crania continua.

Headaches are secondary if at-tributed to an underlying cause such as tumours, infection or inflammation.

Diagnosis

The first step in evaluation is to look for potentially serious pathology. This would be suspected in particular if certain red-flag features are present. (Table 2)

Many individuals with chronic headache are concerned about a brain tumour or stroke. In practice, patients with a stable pattern of headache for 1 year usually do not have significant intrac-ranial lesions. If the cranial magnetic res-onance imaging (MRI) is normal, patients may feel relieved but frustrated because

from their point of view, the pain remains “unexplained”. In few other neurological complaints are detailed history and exam-ination as vital because there are no dis-criminatory laboratory or radiological tests. Once secondary headaches have been excluded, the criteria for primary CDH are clinical and descriptive. The International Headache Society has published a useful but exhaustive classification of headache disorders, which is over 200 pages long plus references, on its website.3

Chronic MigraineOften, chronic migraine is preceded by a history of episodic migraine, which has increased in frequency over months and years until the patient suffers from daily migraneous or nonmigraneous headaches. The characteristic symptoms such as auras, photophobia, phonophobia and nausea may decrease during this transformation period. Risk factors for migraine transformation include female gender, obesity, frequent headaches at baseline and stressful life events.

Chronic Tension-type HeadacheMost patients have bilateral nonthrobbing headache without migraine features such as aura, photophobia or nausea. This usually evolves from episodic tension headache and has a pressing or “tightening” quality. The attacks are not aggravated by walking or head movements.

New Daily Persistent Headache New daily persistent headache (NDPH) is a recently recognized form of primary CDH first described in 1984. It occurs in a person with no past history of headache although this is not an absolute factor. Typically, most patients can recall the exact day on which the pain started, and have experienced daily headache since that time. The diagnostic criteria for NDPH stipulate that pain must be present daily

Table1.Differentialdiagnosisofprimarychronicdailyheadache

Headacheduration>4hours

Chronic migraine•Chronic tension-type headache•New daily persistent headache •Hemicrania continua•

Headacheduration<4hours

With autonomic featuresCluster headache•Paroxysmal hemicrania•Short-lasting unilateral neuralgiform headache •with conjunctival injection and tearing syndrome (SUNCT)

Without autonomic featuresTrigeminal neuralgia•Idiopathic stabbing headache•

Table2.Featuressuggestingasecondarycauseofheadache

Systemic illness•New physical sign •Sudden onset •Onset age >40 years •Progressive worsening of headache•Worst ever headache •Headache worsening with cough•

Journal of The Society of Physicians of Hong Kong 63

References:1. Scher AI, Stewart WF, Liberman J, Lipton RB. Prevalence of frequent

headache in a population sample. Headache 1998;38:497-506.2. Rasmussen BK. Epidemiology of headache. Cephalalgia 1995;15:45-68.3. International Headache Society. HIS Classification ICHD-II. Available

at: http://ihs-classification.org/en/02_klassifikation/02_teil1/04.07.00_other.html. Accessed July 4, 2010.

4. Bigal ME, Rapoport AM, Sheftell FD, et al. Transformed migraine and medication overuse in a tertiary headache centre – clinical character-istics and treatment outcomes. Cephalalgia 2004;24:483-490.

5. Dodick DW. Clinical practice. Chronic daily headache. N Engl J Med 2006;354:158-165.

Table3.Hemicraniacontinua

A.Headacheformorethan3monthsfulfillingthreeothercriteriafromBtoDbelow.

B.Allofthefollowingcharacteristics:

• Unilateralpainwithoutside-shift • Dailyandcontinuous,withoutpain-freeperiods • Moderateintensity,butwithexacerbationsof

severe pain

c.Atleastoneofthefollowingautonomicfeaturesthatoccursduringexacerbationsandisipsilateraltothesideofpain:

• Conjunctivalinjectionand/orlacrimation • Nasalcongestionand/orrhinorrhoea • Ptosisand/ormiosis

D.completeresponsetotherapeuticdosesofindomethacin

E.Notattributedtoanotherdisorder

for more than 2 months with a duration of longer than 4 hours a day. The headaches are usually bilateral in location, and are described as throbbing or pressing in quality, with associated symptoms such as nausea, light sensitivity, sound sensi-tivity, or light-headedness in more than half of the sufferers.

Hemicrania ContinuaThis is an uncommon condition and is a strictly unilateral headache disorder. The definition as adopted by the most recent 2nd edition of the International Classifi-cation of Headache Disorders is in Table 3.2 It is important to recogize this form of CDH as it can be confused with cluster headache, and treatment for it can be quite effective.

Medication overuse HeadacheAll the headache disorders described above can be intensified by the overuse

of prescription or over-the-counter anal-gesics. In fact, the majority of patients who are referred to headache clinics exhibit analgesic overuse. The problem begins with individuals taking one or more drugs to treat headaches over an extended period; this paradoxically leads to more frequent pain and shortening periods between headache recurrence and drug consumption. Patients who consume simple analgesics such as paracetamol or non-steroidal anti-inflam-matory drugs (NSAIDs) for ≥15 days per month are at risk of medication overuse headache. The threshold is reduced to ≥10 days for drugs such as ergotamine, triptans and combination drugs.

Treatment

Treatment of CDH is challenging as usually there is no instant solution and sufferers may have consulted many other doctors and healthcare profes-sionals. The objectives of treatment are to reduce the frequency, severity and duration of attacks, to reduce dis-ability, and to improve daily function. A headache diary is advisable to document the frequency of attacks and analgesic consumption. First-line therapy is with advice on behavioural adjustments such as regular exercise, good sleep hygiene, trigger avoidance, stress reduction and a migraine diet. Some patients may obtain relief from psychotherapy or cognitive behaviour therapy, and there is anecdotal success with yoga and meditation. Medication overuse, if present, should be managed by stopping the offending drugs and using transition therapy with

other analgesics such as NSAIDs or a short course of steroids.4 Sometimes inpatient detoxification regimens can be tried, in which the abused drug should be stopped and preventive drugs started along with anxiolytics, antiemetics and rescue therapy.

The mainstay of treatment of CDH is prophylactic drug therapy; most studies have concentrated on tricyclic an-tidepressants (amitriptyline, nortriptyline), anticonvulsants (valproate, topiramate, gabapentin, pregabalin) and beta-blockers (propranolol, atenolol, metoprolol).5 Se-lective serotonin reuptake inhibitors (fluoxetine) are useful in those with asso-ciated psychiatric comorbidity. Botulinum toxin is expensive but can lead to marked improvement.

Patients who do not respond to first-line treatment may need multiple prophylactic drugs to control headache attacks. Those with refractory headaches may be referred for specialist assessment for review of the diagnosis (to look for unusual causes such as idiopathic in-tracranial hypertension and define the type of headache), and for management of chronic pain and medication overuse. Multidisciplinary care is required for pa-tients with psychiatric morbidity and chemical dependency.

The Editorial Board appreciates your comments and suggestions.

Please send you messages to Dr. Lam Tat Chung, Paul (林達聰醫生)

at drtclam@gmail.com or by fax to 2868 1530